2009A11 Outline the determinants and regulation of extracellular fluid volume.

Body fluid compartments

·  Body is 60% water (42L of 70kg)

·  2/3 ICF (i.e. cytosol) 28L

·  1/3 ECF (i.e. outside cells) 14L. ¼ plasma 3.5L, ¾ ISF 10.5L

·  (others: bone, dense CT, transcellular unimportant to fluid dynamics)

·  Note compartments are functional not anatomical

Determinants of ECF volume

1.                   Amount of Na⁺ in ECF (most important and controllable effective ECF osmole)

a. Na⁺ alone: aldosterone

b. Na⁺ and H₂O: angiotensin 2, ANP

2.                   Tonicity of ECF

a. Water intake: thirst

b. Water output: ADH

Via central blood volume

·  Low pressure baroreceptors in walls of atria and great veins

·  Stretch-activated mechanoreceptors

·  Activation of receptor results in inhibitory signal via CNX afferents

Via systemic arterial pressure

·  Carotid and aortic sinus baroreceptors

·  ↓mAP -> ↓stretch -> ↓inhibition of output to hypothalamus via CNIX (carotid) and CNX (aortic)

Via renal afferent arteriolar pressure

·  Renal baroreceptors

·  ↓mAP -> ↓stretch -> ↓inhibition of granular cell -> ↑renin release

Brain

·  Hypothalamus controls ECF sodium content and tonicity

Kidney

·  Juxtaglomerular apparatus controls ECF sodium content

RAAS

·  Stimuli for renin release:

o ↑SNS activation of granular cells (β₁)

o ↓stretch of afferent arteriolar baroreceptors

o ↓NaCl delivery to macula densa

·  Stimuli for aldosterone release:

o ACTH

o Angiotensin 2

o ↑K⁺

·  Actions of angiotensin 2:

o Renal:

§ ↑Activity proximal tubule Na⁺/H⁺ exchanger

§ ↑Na⁺/H₂O/HCO₃^- reabsorption

§ ↑ECF volume and pH

o Vascular

§ Peripheral vasoconstriction -> ↑SVR, mAP

§ Constriction of efferent > afferent -> ↑GFR

§ Constriction of peritubular capillaries -> ↑reabsorption

o Hypothalamic

§ Thirst

§ ADH release

·  Actions of aldosterone (most important factor):

o Na⁺ reabsorption from connecting tubule and collecting ducts (MR)

o Na⁺ reabsorption from colon, sweat glands (MR)

o ↑ECF tonicity directly

o ↑ECF volume indirectly (↑osmolarity -> ↑ADH release)

·  Negative feedback:

o Direct: AT2 binds AGTR1 on granular cell -> ↑Ca2+ -> ↓renin release

o Physiological: effects of AT2 and aldosterone -> ↓renin release

ANP

·  Stimulus:

o Distension of right atrium (i.e. ↑central blood volume)

·  Effects:

o Dilatation of afferent arteriole, constriction of efferent arteriole -> ↑GFR

o Inhibit NCC in distal tubule, ENaC in connecting tubule and collecting duct -> ↓Na⁺/H₂O reabsorption

o i.e. natriuresis

o ↓ECF volume

ADH

·  Production: hypothalamus (supra-optic and paraventricular nuclei)

·  Release: posterior pituitary

·  Stimuli:

o ↑osmolality (sensitive to ∆2%)

o ↓BV (sensitive to ∆10% i.e. ↓BV 0.5L, ↓ECF 1.4L, ↓TBW 4L; overrides osmolarity)

o ↓mAP

o Angiotensin 2

o Stress (e.g. surgery)

o Drugs (e.g. SSRI)

·  Effects:

o Insertion of aquaporins into collecting duct apical membranes (↑free H₂O reabsorption)

o Insertion of ureaporins into medullary collecting duct apical membranes (↑medullary interstitial osmolarity)

o (Other: generalized vasoconstriction, ↑ACTH release)

o ↑ECF volume and ICF volume

Thirst

·  Stimuli: as for ADH (except for stress response and drugs)

o ↑Osmolality

o ↓Blood volume

o ↓mAP

o Angiotensin 2 at SFO and OVLT

·  Effect:

o ↑free water intake

o ↑ECF volume and ICF volume